Nitroxoline is an antimicrobial agent which has been commercially marketed for a long time for the treatment of urinary tract infections. It was recently discovered that nitroxoline is also active in inhibiting angiogenesis [1] and inhibiting the growth and invasion of cancer [2, 3].
Nitroxoline is orally administered to patients. Pharmacokinetic studies in humans indicated that nitroxoline can be rapidly absorbed into the blood for circulation [4]. Nitroxoline has a very short half-life (t1/2) in humans, with the t1/2=2.63 hour. Thus, nitroxoline is quickly metabolized and excreted, mainly through urine. Therefore, to maintain continuous drug exposure, nitroxoline drug products are usually prescribed at three times a day (TID) or four times a day (QID).
Nitroxoline also has low solubility in water. Therefore, it is typically prepared in immediate-release formulations, which allows for the release of nitroxoline in gastric liquids in the stomach, and subsequent absorption in the intestine. Although the crystal structure of a hydrochloride (HCl) addition salt of nitroxoline has been reported by Yatsenko et al. [5], no solubility data of any nitroxiline salts, including the nitroxoline HCl salt, have been disclosed. Due to the low water solubility of nitroxoline, no controlled release formulations of nitroxoline or injectable formulations of nitroxiline have been reported or developed for human uses to date.
Novel salts of nitroxoline with improved water solubility would provide for the development of optimized drug formulations of nitroxoline, which would allow patients to be administered such nitroxoline drugs formulations with less frequency, thereby improving the compliance of drug administration. Drug dosing compliance is critical to warrant the drug's adequate exposure and bioavailability in patients, and hence its efficacy in treating diseases. A steadier drug level in the blood stream delivered by an optimized formulation may also reduce adverse effects. An improved solubility in water would further enable the preparation of nitroxoline salts in liquid compositions.
Novel salts of nitroxoline with improved stability would also provide for the development of optimized drug formulations and improve the manufacturing process. Nitroxoline sublimes at high temperatures [6], which causes several problems in the process of manufacturing. For example, sublimed nitroxoline causes contamination during the drying process by accumulating on the surfaces of the manufacturing place and equipment. Thus, when manufactured into tablets, for example, nitroxoline may penetrate the coating films and contaminate the containers.
Accordingly, there exists a need in the art for novel salts of nitroxoline that have improved water solubility and improved stability as compared to nitroxoline.